Objectives: K-Ras is a normal cellular protein. Oncogenic K-Ras mutation, leading to the exacerbated activation of K-Ras protein, causes tumor initiation and progression. K-Ras mutation is found in more than 25% of human non-small cell lung carcinomas (NSCLC). However, lung cancers caused by K-Ras mutation are generally refractory to chemotherapy as well as targeted agents. Moreover, the identification of drugs to therapeutically inhibit K-Ras has been unsuccessful, suggesting that other approaches are required. Sphingosine-1-phosphate (S1P) is an important lipid mediator present in our body. Levels of S1P receptor subtype 3 (S1PR3, a receptor which binds S1P and mediates S1P functions) are increased in lung carcinomas. S1PR3 regulates various tumorigenic functions which are critical for the progression of human lung adenocarcinoma (LADC). Inhibition of S1PR3 profoundly diminishes lung carcinoma growth in animals. Furthermore, oncogenic K-Ras mutant stimulates S1PR3 expression in vitro and in vivo. Collectively, the objectives of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC, and to investigate whether S1PR3 inhibition provides an effective therapy for K-Ras mutant-driven human LADC. Hypothesis, Specific aims, and Study designs: The hypothesis of this proposal is ?Exacerbated S1PR3 activity contributes to oncogenic K-Ras mutant-driven LADC progression, at least in part, by promoting macrophage infiltration to LADC. S1PR3 represents a potential therapeutic target for the treatment of K-Ras mutant-driven LADC.? Two aims are proposed to test this hypothesis. Aim 1. A genetically engineered mouse strain, mice expressing mutated K-Ras protein and lacking S1PR3, will be utilized to determine the critical role of S1PR3 in K-Ras mutant-driven LADC. In addition, the role of S1PR3 in recruiting inflammatory macrophages to LADC will be investigated. Aim 2. TY-52156, a highly selective S1PR3 antagonist, will be used to demonstrate the proof-of-concept that S1PR3 inhibition is an effective intervention for oncogenic K-Ras mutant-driven LADC. Health relatedness of the project: Lung cancer remains the leading cause of cancer-related deaths. The main goal of this application is to characterize the critical role of S1PR3 in K-Ras mutant-driven LADC progression. The successful completion of this application is expected to provide multiple intervention points for the fight against oncogenic K-Ras mutant-driven LADC in the future.